KR101005717B1 - HFA-Suspension formulation of an anhydrate - Google Patents

Abstract

The present invention relates to (1α, 2β, 4β, 5α, 7β) -7-[(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [ 3.3.1.0 ^2,4 ] Propellant formulations containing a suspension of crystalline anhydride of nonane bromide.

Quantitative aerosols, propellant gases, tiotropium bromide, anticholinergic, asthma, chronic obstructive pulmonary disease

Description

HFA-Suspension formulation of an anhydrate             

The present invention relates to (1α, 2β, 4β, 5α, 7β) -7-[(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [ 3.3.1.0 ^2,4 ] Propellant gas formulations for quantitative aerosols having a suspension formulation of crystalline anhydride of nonan-bromide.

Compound (1α, 2β, 4β, 5α, 7β) -7-[(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3. 1.0 ^2,4 ] Nonane-bromide is known from European patent application EP 418 716 A1 and has the formula:

The compound has beneficial pharmaceutical properties and is known under the name tiotropium bromide (BA679). Tiotropium bromide is a very effective anticholinergic and can be therapeutically beneficial in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Tiotropium bromide is preferably administered by inhalation.

It is an object of the present invention to prepare HFA-quantitative aerosols containing tiotropium bromide in suspension form as a single active ingredient.

Depending on the choice of conditions that can be used, it has been found that when purifying the crude product obtained after industrial production, tiotropium bromide occurs with various crystalline modifications.

It has been found that these different variants can be intentionally produced by the selection of the solvent used for the crystallization as well as by the appropriate choice of the process conditions used during the crystallization process. One such crystalline modification is crystalline monohydrate of tiotropium bromide.

Surprisingly, the present invention starts with crystalline monohydrate of tiotropium bromide, which is not yet known in the art, and is very suitable for preparing suspensions in propellant gas HFA 227 and / or HFA 134a for administration by inhalation. It has been found that anhydrous crystalline modifications of um bromide (thiotropium anhydride) can be obtained.

Accordingly, the present invention preferably provides propane, butane, pentane, dimethyl ether, CHClF ₂ , CH ₂ F ₂ , To a suspension of the crystalline thiopromium bromide in the propellant gas HFA 227 and / or HFA 134a, optionally mixed with one or more other propellant gases selected from the group consisting of CF ₃ CH _3, isobutane, isopentane and neopentane. It is about.

When referring to crystalline tiotropium bromide anhydride within the scope of the present invention, it should be understood to refer to anhydrous crystalline modifications of tiotropium bromide which can be obtained by drying the crystalline tiotropium bromide monohydrate. do. Such crystal modifications are also known as crystalline tiotropium bromide, optionally in anhydride form, within the scope of the present invention.

Preferred suspensions according to the invention are those which contain only the propellant gas HFA 227 itself, a mixture of HFA 227 and HFA 134a or only HFA 134a itself. When a mixture of propellant gases HFA 227 and HFA 134a is used in the suspension formulation according to the invention, the weight ratio of the two propellant gas components can be freely selected. In addition to the propellant gases HFA 227 and / or HFA 134a in suspension formulations according to the invention, propane, butane, pentane, dimethylether, CHClF ₂ , CH ₂ F ₂ , When one or more other propellant gases selected from the group consisting of CF ₃ CH _3, isobutane, isopentane and neopentane are used, the proportion of said other propellant gas components is preferably less than 50%, preferably 40%. Less than 30%, more preferably less than 30%.

The suspension according to the invention preferably contains from 0.001 to 0.8% tiotropium. Preferred according to the invention are suspensions containing 0.08 to 0.5%, more preferably 0.2 to 0.4% tiotropium.

Tiotropium means free ammonium cation. The propellant gas suspension according to the invention is characterized by containing tiotropium in the form of crystalline tiotropium bromide anhydride which is well suited for such applications. Accordingly, the present invention preferably relates to suspensions containing 0.0012 to 96% crystalline tiotropium bromide anhydride. Particularly advantageous according to the invention are suspensions containing from 0.096 to 0.6%, more preferably from 0.24 to 0.48% of crystalline tiotropium bromide anhydride.

The percentages specified within the scope of the invention are always mass%. If the mass part of tiotropium is given in mass%, the corresponding value of the crystalline tiotropium bromide anhydride which is preferably used within the scope of the present invention can be obtained by multiplying the conversion factor of 1.2036.

In some cases within the scope of the present invention, the term suspension formulation may be used instead of the term suspension. The two terms should be considered interchangeable within the scope of the present invention.

Propellant-containing inhalation aerosols or suspension formulations according to the invention may also contain other ingredients such as surface-active agents (surfactants), adjuvants, antioxidants or perfumes.

Surface-active agents (surfactants) which may be contained in the suspensions according to the invention are preferably polysorbate 20, polysorbate 80, mibaset 9-45, mibaset 9-08, isopropyl myristate, oleic acid, Propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetyl alcohol, Stearyl alcohol, cetylpyridinium chloride, block polymer, natural oil, ethanol and isopropanol. As auxiliaries in the above-mentioned suspensions, polysorbate 20, polysorbate 80 , mibaset 9-45, mibaset 9-08 or isopropyl myristate are preferably used. Mibaset 9-45 or isopropyl myristate is particularly preferred.

If the suspension according to the invention contains a surfactant, it is preferably present in an amount of 0.0005 to 1%, more preferably 0.005 to 0.5%.

Adjuvants optionally contained in the suspensions according to the invention are preferably selected from alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid. Among these, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are preferable, and hydrochloric acid or citric acid is more preferable.

If the suspension according to the invention contains an adjuvant, it is preferably present in an amount of 0.0001 to 1.0%, preferably 0.0005 to 0.1%, more preferably 0.001 to 0.01% and an amount of 0.001 to 0.005% Particular preference is given according to the invention.

Antioxidants optionally contained in the suspensions according to the invention are preferably selected from ascorbic acid, citric acid, sodium edetate, editic acid, tocopherol, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate Among them, tocopherol, butylhydroxytoluene, butylhydroxyanisole or ascorbyl palmitate is preferable.

The fragrances which may be contained in the suspension according to the invention are preferably selected from peppermint, saccharin, dentomint (Dentomint ^® ), aspartame and ethereal oils (cinnamon, anise fruit, menthol, camphor), among which peppermint or Dentomint is particularly preferred.

For administration by inhalation, it is necessary to prepare finely divided active substances. Crystalline tiotropium bromide anhydride, which can be obtained as detailed in the experimental part, is obtained in fine form by grinding (micronization) or by other technical methods basically known in the art (eg precipitation and spray drying). . Methods of micronizing the active substance are known in the art. Preferably, after micronization, the average particle size of the active substance is 0.5 to 10 μm, preferably 1 to 6 μm, more preferably 1.5 to 5 μm. Preferably, at least 50%, more preferably at least 60% and most preferably at least 70% of the particles of the active substance have a particle size within the range specified above. More preferably, at least 80% and most preferably at least 90% of the particles of the active substance have a particle size within the range specified above.

Surprisingly, it has also been found possible to prepare suspensions, apart from the abovementioned propellant gases, which contain only the active substance and no other additives. Thus, in another aspect, the present invention relates to a suspension containing only the active substance without other additives.

Suspensions according to the invention can be prepared by methods known in the art. To this end the components of the formulation are mixed with the propellant gas or gases (optionally at low temperatures) and transferred into a suitable container.

The propellant gas-containing suspensions according to the invention mentioned above can be administered using inhalers known in the art (pMDIs = pressurized metered dose inhalers). Thus, in another aspect, the invention relates to a pharmaceutical composition in suspension form as described above in combination with one or more inhalers suitable for administering such suspensions. The invention also relates to an inhaler characterized in that it contains the propellant gas-containing suspension described above according to the invention. The invention also relates to a container (cartridge) equipped with a suitable valve and used in a suitable inhaler and containing one of the abovementioned propellant gas suspensions according to the invention. Suitable containers (cartridges) and methods for filling said cartridges with the propellant gas containing suspension according to the invention are known from the prior art.

In view of the pharmaceutical activity of tiotropium, the present invention further provides for the preparation of a medicament for administration by the inhalation or nasal route, preferably the treatment by the inhalation or nasal route of diseases in which anticholinergic agents may be therapeutically beneficial. It relates to the use of the suspension according to the invention in the preparation of a medicament.

Most preferably, the present invention further relates to the use of the suspensions according to the invention for the preparation of pharmaceutical compositions for the treatment of respiratory diseases, preferably asthma or COPD by inhalation.

The following examples more fully illustrate the invention by way of example, but do not limit the content thereof.

Starting material

Crystalline Tiotropium Bromide Monohydrate:

Tiotropium obtained according to EP 418 716 A1 can be used to prepare crystalline tiotropium bromide monohydrate. This is then reacted as described below.

15.0 kg of tiotropium bromide is added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C. and stirred at a constant temperature until a clear solution is formed. Activated charcoal (0.8 kg) moistened with water is suspended in 4.4 kg water and the mixture is added to a solution containing tiotropium bromide and rinsed with 4.3 kg water. The mixture thus obtained is stirred at 80 to 90 ° C. for at least 15 minutes and then filtered through a heated filter to a device preheated to an external temperature of 70 ° C. The filter is rinsed with 8.6 kg of water. The contents of the device are cooled to a temperature of 20-25 ° C. at a rate of 3-5 ° C. every 20 minutes. The crystallization is completed by cooling the apparatus further to 10-15 ° C. with cold water and stirring for additional 1 hour or more. The crystals are separated using a suction filtration dryer, and the separated crystal slurry is washed with 9 L of cold water (10-15 ° C.) and cold acetone (10-15 ° C.). The obtained crystals are dried at 25 ° C. for 2 hours under nitrogen flow. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).

Thiotropium bromide monohydrate obtainable using the method described above was investigated by DSC (Differential Scanning Calorimetry). DSC plots show two characteristic signals. The relatively broad endothermic signal between 50 and 120 ° C. may be due to the dehydration of tiotropium bromide monohydrate to form an anhydride. A relatively steep second endothermic peak at 230 ± 5 ° C. may be due to the melting of the material. The data were obtained using Mettler DSC 821 and evaluated using the Mettler STAR software package. Data was recorded at a heating rate of 10 K / min.

Crystalline tiotropium bromide monohydrate was characterized by IR spectroscopy. Data was obtained using a Nicolet FTIR spectrometer and evaluated with Nicolet OMNIC software 3.1 version package. Evaluation was performed using 2.5 μmol of tiotropium bromide monohydrate in 300 mg KBr. The table below shows some of the essential bands of IR spectroscopy.

Frequency (cm ^-1 ) property Oscillation Type 3570, 3410 O-H Long vibration 3105 Aryl C-H Long vibration 1730 C = O Long vibration 1260 Epoxide C-O Long vibration 1035 Ester C-OC Long vibration 720 Thiophene Annular vibration

The single crystal X-ray structure analysis performed showed that the crystalline tiotropium bromide hydrate obtainable by the method had a simple monoclinic cell having the following characteristics:

a = 18.0774 kPa, b = 11.9711 kPa, c = 9.9321 kPa, β = 102.691 °, V = 2096.96 kPa ³ .

These data were obtained using an AFC7R four-circuit diffractometer (Rigaku) using monochromatic copper K _α radiation. Structural resolution and purification of the crystal structure were obtained by direct methods (SHELXS86 program) and FMLQ purification (TeXsan program).

Crystalline Tiotropium Bromide Anhydride:

Anhydride forms are produced by carefully drying from crystalline tiotropium bromide monohydrate obtained as described above at least at least 30 minutes at 80 to 100 ° C. under reduced pressure, preferably under high vacuum. As an alternative to the drying step of 80-100 ° C. under vacuum, anhydride forms can also be prepared by storing on dry silica gel at ambient temperature over at least 24 hours.

The crystalline structure of anhydrous tiotropium bromide was measured from high-resolution X-ray powder data (synchrotron radiation) by the actual spatial mixture using the so-called "simulating annealing" method. Final Rietveld analysis was performed to improve the structural parameters. This investigation indicated that the crystalline tiotropium bromide anhydride used in the suspension according to the invention is characterized by the following elementary cells:

a = 10.4336 (2)

b = 11.3297 (3)

c = 17.6332 (4)

α = 90 °

β = 105.158 (2) ° and

γ = 90 ° (cell volume = 2011.89 (8) Å ³ ).

In order to prepare the suspension according to the invention, the crystalline tiotropium bromide anhydride obtainable by the above method is micronized while excluding water by a method known in the art, so that the average particle size corresponding to the specification according to the present invention. The active substance is prepared in the form of.

Examples of Formulations

Suspensions containing other ingredients in addition to the active and propellant gases:

a) 0.02% tiotropium *

    0.20% Polysorbate 20

   99.78% HFA 227                 

b) 0.02% tiotropium *

    1.00% Isopropyl Myristate

   98.98% HFA 227

c) 0.02% tiotropium *

     0.3% Mivasette 9-45

   99.68% HFA 227

d) 0.04% tiotropium *

    1.00% Mibaset 9-08

   98.96% HFA 227

e) 0.04% tiotropium *

    0.04% Polysorbate 80

   99.92% HFA 227

f) 0.04% tiotropium *

   0.005% oleic acid

  99.955% HFA 227

g) 0.02% tiotropium *

     0.1% Mibaset 9-45

   60.00% HFA 227

   39.88% HFA 134a

h) 0.02% tiotropium *                 

    0.30% Isopropyl Myristate

   20.00% HFA 227

   79.68% HFA 134a

i) 0.02% Tiotropium *

    0.01% oleic acid

   60.00% HFA 227

   39.97% HFA 134a

* Used in the form of tiotropium bromide anhydride (conversion factor 1.2036)

Suspensions containing only the active ingredient and the gas for propulsion:

j) 0.02% Tiotropium *

   99.98% HFA 227

k) 0.02% tiotropium *

   99.98% HFA 134a

l) 0.04% tiotropium *

   99.96% HFA 227

m) 0.04% tiotropium *

   99.96% HFA 134a

n) 0.02% tiotropium *

   20.00% HFA 227                 

   79.98% HFA 134a

o) 0.02% tiotropium *

   60.00% HFA 227

   39.98% HFA 134a

p) 0.04% tiotropium *

   40.00% HFA 227

   59.96% HFA 134a

q) 0.04% tiotropium *

   80.00% HFA 227

   19.96% HFA 134a

* Used in the form of tiotropium bromide anhydride (conversion factor 1.2036)

Claims (10)

A suspension of crystalline tiotropium bromide anhydride in propellant gas HFA 227, HFA 134a or both, wherein the crystalline tiotropium bromide anhydride is a = 10.4336 (2) ', b = 11.3297 (3)', c = Suspension characterized by unit cells of 17.6332 (4) 'and α = 90 °, β = 105.158 (2) ° and γ = 90 °, cell volume = 2011.89 (8)' ³ . A suspension according to claim 1, which contains from 0.001 to 0.8% by mass of crystalline tiotropium bromide anhydride. The suspension according to claim 1 or 2, which contains, as other components, at least one component selected from the group consisting of surface-active agents (surfactants), adjuvants, antioxidants and fragrances. The method according to claim 3, wherein the surface-active agent (surfactant) is polysorbate 20, polysorbate 80, Myvacet 9-45, mibaset 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene Glycols, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monosterate, glyceryl monoricinoleate, cetyl alcohol, steryl alcohol, A suspension characterized in that it contains at least one compound selected from the group consisting of cetylpyridinium chloride, block polymer, natural oil, ethanol and isopropanol. 4. A suspension according to claim 3, which contains at least one compound selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid as an adjuvant. The method of claim 3, wherein the antioxidant contains at least one compound selected from the group consisting of ascorbic acid, citric acid, sodium edetate, edetic acid, tocopherol, butylhydroxytoluene, butylhydroxyanisole and ascorbyl palmitate. Suspension characterized in that. A suspension according to claim 1 or 2, characterized in that it consists of the active substance and the propellant gas or gases. A suspension according to claim 1 or 2 for the preparation of a pharmaceutical composition for treatment by inhalation or nasal route of asthma or COPD (chronic obstructive pulmonary disease). delete According to claim 1, Propane, butane, pentane, dimethyl ether, CHClF ₂ , CH ₂ F ₂ , A suspension characterized in that it further contains at least one other propellant gas selected from the group consisting of CF ₃ CH _3, isobutane, isopentane and neopentane.